Ventrolateral Medulla AT ₁ Receptors Support Blood Pressure in Hypertensive Rats

Abstract

Abstract-Angiotensin within the central nervous system appears to be important for the maintenance of hypertension in spontaneously hypertensive rats. This study addresses the hypothesis that blockade of AT 1 receptors in the rostral ventrolateral medulla would decrease blood pressure in spontaneously hypertensive rats and that this tonically active AT 1 -mediated input to the rostral ventrolateral medulla arises from the hypothalamic paraventricular nucleus. Injection of the nonpeptide AT 1 receptor antagonist valsartan bilaterally into the rostral ventrolateral medulla of choralose-anesthetized adult spontaneously hypertensive rats produced a dose-related decrease in mean arterial pressure, with a maximal effect of Ϸ30 mm Hg. Inhibition of the paraventricular nucleus by local injection of muscimol elicited a similar response, which was inhibited by prior injection of valsartan into the rostral ventrolateral medulla. In contrast, in control Wistar-Kyoto rats, neither valsartan injected into the rostral ventrolateral medulla nor muscimol injected into the paraventricular nucleus had a substantial effect on arterial pressure. These data indicate that in spontaneously hypertensive rats but not in Wistar-Kyoto rats, rostral ventrolateral medulla vasomotor neurons are tonically excited by endogenous stimulation of AT 1 receptors, and this input is apparently driven from the hypothalamus. These results suggest that the rostral ventrolateral medulla is one site that the brain renin-angiotensin system acts to maintain elevated blood pressure in spontaneously hypertensive rats. The data supporting of a role of brain Ang II in hypertension in the spontaneously hypertensive rats (SHR) are particularly convincing. Specifically, pharmacological disruption of brain angiotensin signaling decreases AP in SHR. 6 -10 Furthermore, there appear to be alterations in SHR in the amount of angiotensin or its receptors in discrete brain regions. 3,4,11,12 Despite this important role of brain Ang II in hypertension, the site (or sites) within the brain at which Ang II acts in this regard is not fully worked out. Certainly, Ang II can act within the hypothalamus to influence cardiovascular regulation. 13 However, Ang II can also act in the caudal brain stem to increase AP and sympathetic outflow. 14 One region in the caudal brain stem that probably mediates some of the central cardiovascular effects of Ang II is the rostral ventrolateral medulla (RVLM). 15,16 The RVLM appears to be the brain site responsible for the maintenance of basal sympathetic vasomotor activity, and inhibition of RVLM neurons reduces AP to the same extent as total inhibition of sympathetic vasomotor activity. Conversely, stimulation of neurons in the RVLM increases AP. There is evidence that increased activity of the RVLM supports the elevated AP in SHR. [17][18][19] The RVLM also has a high density of angiotensin AT 1 receptors. 20 Furthermore, microinjection of Ang II into the RVLM increases AP and sympathetic nerve activity, [21][22][23][24] and stimulation of A...

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

“…11,14,15 Direct inhibition of the AT 1 R in the RVLM inhibits SNS activation in hypertensive rats. 15,[18][19][20] Peripherally administered ARBs also inhibit the central actions of angiotensin II in the brain. [21][22][23][24][25][26][27][28] Furthermore, we demonstrated that orally administered TLM inhibits SNS activation by reducing oxidative stress in the brains of hypertensive rats.…”

“…22,24,25,28 Direct inhibition of AT 1 R in the RVLM or other areas of the brain inhibits SNS activation, 15,[18][19][20] and superfusion with CAN decreases the electrophysiological activity of RVLM neurons examined using the patch-clamp technique. 42 In previous studies demonstrating sympathoinhibition caused by orally administered CAN in hypertensive rats, the doses of CAN were greater (4, (ref.…”

“…6,7 Microinjection of AT 1 R blockers (ARBs) into the RVLM or intracerebroventricular infusion of ARBs inhibits SNS activation in hypertensive rats. 15,[18][19][20] However, AT 1 R or oxidative stress in the RVLM have not been targets for the treatment of hypertensive patients because we do not have suitable oral agents to inhibit AT 1 R or oxidative stress in the RVLM of hypertensive patients.…”

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

“…[18][19][20] For example, both the pressor response to the microinjection of angiotensin II into the RVLM and the stimulation of AT 1 receptors were enhanced in spontaneously hypertensive rats (SHRs). 21 The activation of endogenous AT 1 receptors has also been demonstrated in SHRs and stroke-prone spontaneously hypertensive rats (SHRSPs). 22,23 It has been reported that microinjection of aldosterone into the RVLM increases AP, and that the MR blocker spironolactone decreases AP.…”

Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

“…In spontaneously hypertensive rats, Dahl-saltsensitive rats, and renal injury hypertensive rats, the elevated SNA is associated with an increase in the tonic activation of the RVLM by glutamate and angiotensin II (2,9,17,18,19,20). In addition, reduced tonic GABAergic inhibition of the RVLM also appears to contribute to the elevated MAP observed in spontaneously hypertensive rats (38).…”